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PubMed1999

Expression of granulocyte colony-stimulating factor- and granulocyte-macrophage colony-stimulating factor-associated signal transduction proteins of the JAK/STAT pathway in normal granulopoiesis and in blast cells of acute myelogenous leukemia.

Acute myelogenous leukemia (AML) is characterized by the malignant transformation of hematopoietic stem cells leading to dysregulated growth and differentiation of myeloid cells. Normally, proliferation and differentiation of myeloid cells are regulated by cytokines such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). Abnormal signaling of the signal transduction pathway from the cytokine receptors via Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) might be involved in the pathogenesis of AML. We examined whether an abnormal expression of one of the four JAKs, STAT1, STAT3, STAT5, or the tyrosine phosphatase SHP-1, a negative regulator of this pathway, is associated with malignant transformation in AML. Analysis of the expression of proteins of the JAK/STAT pathway in normal myeloid cells at three stages of maturation revealed a strong expression of all proteins in CD34+ cells, whereas the level of the proteins was significantly lower in granulocytic precursors and mature neutrophils. Furthermore, during maturation the relation of the isoforms of STAT1 and STAT3 changed from predominantly alpha to predominantly beta. Leukemic blast cells from 25 patients and 12 cell lines showed a high level of STAT proteins and SHP-1, whereas a deficiency of at least one of the four JAKs was found in 10 of 25 patients. In primary AML blast cells a deficiency of three JAKs was more common in patients with an abnormal karyotype. In addition, a lack of JAK2 and Tyk2 protein was strongly associated with the FAB M2 phenotype. The proliferation rate in response to GM-CSF available in a small number of patients appears to be related to the JAK2 expression. Our data suggest that the degree of expression of G-CSF/GM-CSF receptor-associated proteins of the JAK/STAT pathway in normal myeloid cells is related with their clonogenic potential. STAT3 appears to be involved in early differentiation. Similar to CD34+ cells, it is likely that the high levels of STATs and SHP-1 found in leukemic cells reflects their proliferative activity, whereas a lack of members of the JAK family might lead to an inability to proliferate in response to G-CSF/GM-CSF described in a considerable percentage of AML blasts.

Antigens, CD34↗
PubMed1998

Replating potential of colony-forming units of granulocytes/macrophages (CFU-GM) expanded ex vivo by stem cell factor, interleukin (IL)-3, IL-6, granulocyte colony-stimulating factor, erythropoietin with or without thrombopoietin.

Ex vivo expansion systems of hematopoietic progenitor cells (HPC) have been extensively studied and their clinical application is under investigation. However, it is not known whether HPC expanded ex vivo will be able to retain their replating potential. CD34+ cells isolated from cord blood were cultured in Iscove's modified Dulbecco's medium supplemented with 10% fetal bovine serum, 1.0% bovine serum albumin, 50 ng/ml stem cell factor, 50 ng/ml interleukin-3 (IL-3), 50 ng/ml IL-6, 100 ng/ml granulocyte colony-stimulating factor, and 3 U/ml erythropoietin for 0, 5, 7, 10, 14, and 21 days. After the expansion cultures, granulocyte/macrophage progenitor cells (CFU-GM) were assayed from each culture by the standard methylcellulose method. After 14 days of culture, CFU-GM-derived colonies were randomly picked up and processed for the replating assay. The fold increase of CFU-GM peaked at day 7 of the expansion culture (29.8 +/- 7.7-fold, n = 5), followed by a decline until day 21. In the replating assay of CFU-GM from freshly isolated CD34+ cells, the mean replating efficiency was 91.2 +/- 4.7%. The replating efficiency decreased gradually with the time of the expansion culture. At day 7 when the fold increase of CFU-GM reached its peak, the replating efficiency had dropped to 47.5 +/- 2.3%, followed by a further decline to 5.3 +/- 3.4% at day 21. Furthermore, the addition of 100 ng/ml thrombopoietin to this expansion system failed to prevent the decline of replating efficiency. These observations suggest that the replating potential of CFU-GM may decrease in the ex vivo expansion system, even when their fold increase reaches its peak. This should be taken into consideration when HPC expanded ex vivo are used in clinical transplantation.

Antigens, CD34↗
PubMedDate not supplied

Outcomes of granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor use in neutropenic patients infected with human immunodeficiency virus.

OBJECTIVE: To characterize the effects of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) on clinical outcomes in neutropenic HIV-infected patients, by means of a retrospective cohort study at an urban teaching hospital. METHOD: Data were reviewed from all patients discharged between January 1, 1996, and August 31, 1997, with human immunodeficiency virus and neutropenia (absolute neutrophil count (ANC) <1000 cells/mL), with outcome measures of length of stay, infectious complications, and survival to discharge. RESULTS: Of the 228 discharged patients who met selection criteria, 71 had received G-CSF or GM-CSF; 157 controls had not. Cases had lower CD4+ cell counts (30 vs. 54 cells/mL; P = 0. 017) and lower nadir ANCs (372 vs. 579 cells/mL; P < 0.001). Granulocyte-CSF or GM-CSF usage was not associated with the frequency of site-related infections, fever, or sepsis (all P > 0. 20). No difference was found in duration of hospitalization (23 vs. 21 days; P > 0.20). In a logistic regression model for survival to discharge, higher nadir ANC and CSF use were independently associated with improved survival (P = 0.034 and P = 0.026, respectively). CONCLUSION: Use of G-CSF or GM-CSF was associated with improved survival to discharge among hospitalized HIV-infected patients with neutropenia.

AIDS-Related Opportunistic Infections↗
PubMed2003

Engraftment syndrome after autologous hematopoietic stem cell transplant supported by granulocyte-colony-stimulating factor (G-CSF) versus granulocyte-macrophage colony-stimulating factor (GM-CSF).

The engraftment syndrome (ES) is a phenomenon observed in some patients undergoing autologous hematopoietic stem cell transplant (AHSCT). ES is characterized by fever, rash, capillary leak, and pulmonary infiltrates occurring at the onset of engraftment. Prior studies have suggested that the administration of hematopoietic growth factors post-transplant results in the increased frequency of ES. However, the relative contribution of granulocyte colony-stimulating factor (G-CSF) vs granulocyte-macrophage colony-stimulating factor (GM-CSF) to the development of ES remains unknown. A total of 152 consecutive patients who were treated with high-dose chemotherapy and AHSCT supported by either G-CSF or GM-CSF were analyzed retrospectively. In all, 20 patients developed ES, an incidence of 13%. ES was seen more frequently in patients who received GM-CSF (GM-CSF 24% vs G-CSF 4%, p=0.0001). The highest incidence of ES was observed in breast cancer patients (42% of breast cancer patients; 70% of all ES cases). Comparison of the incidence of ES by the priming regimen used comprising either of the growth factors revealed no significant association (p=0.8224). This study demonstrates that the incidence of ES is higher using GM-CSF, particularly in patients with breast cancer. It suggests that it might be advantageous to administer only G-CSF in breast cancer patients undergoing AHSCT to reduce ES-related morbidity.

Adult↗
PubMed2005

Concurrent administration of granulocyte colony-stimulating factor or granulocyte-monocyte colony-stimulating factor enhances the biological activity of rituximab in a severe combined immunodeficiency mouse lymphoma model.

A predominant percentage of the in vivo antitumor activity of rituximab occurs through antibody-dependent cellular cytotoxicity (ADCC) via FcgammaRIII receptors. Co-expression of CD11b/CD18 (MAC-1), an adhesion molecule present in activated neutrophils, plays an important role in the induction of ADCC. The effects of granulocyte-monocyte colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on the biological activity of rituximab were studied in a non-Hodgkin's lymphoma (NHL)-bearing severe combined immunodeficiency (SCID) mouse model. Natural killer (NK) cell-depleted SCID mice were inoculated intravenously with Raji cells. Animals were divided into 6 cohorts: group A: placebo (saline injection); group B: murine (m)-G-CSF; group C: m-GM-CSF; group D: rituximab alone; group E: concurrent m-G-CSF and rituximab; and group F: concurrent m-GM-CSF and rituximab. Treatment with G-CSF or GM-CSF led to a 1.5- to 2-fold increase of CD11b/CD18 expression in neutrophils. Treatment with G-CSF led to the highest expression of CD11b/CD18 on neutrophils. No antitumor activity was observed among mice treated with G-CSF or GM-CSF alone. After 3 months, survival rates were highest in animals treated with rituximab and G-CSF (53.3%) compared to rituximab alone (13.3%) or in combination with peg-GM-CSF (26.7%). Increasing neutrophil counts via cytokine stimulation may play an important role in augmenting rituximab-associated antitumor activity.

Animals↗
PubMed2002

Effect of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on polymorphonuclear neutrophils, monocytes or monocyte-derived macrophages combined with voriconazole against Cryptococcus neoformans.

The antifungal activity of voriconazole (VCZ) was tested against Cryptococcus neoformans (Cn) with and without the addition of polymorphonuclear neutrophils (PMN), monocytes or monocyte-derived macrophages (MDM) in vitro. Human effector cells with and without the addition of VCZ were incubated with Cn for 24 h. PMN, mono and MDM alone resulted in 61%, 34% and 23% inhibition of Cn, respectively (n = 3, P<0.01). VCZ at 0.01 and 0.05 microg ml(-1) alone resulted in 48% inhibition and 19% killing (n = 6). The addition of VCZ at 0.01 and 0.05 microg ml(-1) to human effector cells enhanced killing of Cn by 51% and 71% for the PMN, 41% and 58% for the mono, and 14% and 34% for the MDM, respectively. The addition of either granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) significantly enhanced the ability of human effector cells to kill Cn. G-CSF and GM-CSF plus PMN resulted in 47% and 46% killing, respectively; GM-CSF plus monocytes or MDM resulted in 31% or 22% killing, respectively. G-CSF and GM-CSF further enhanced the collaborative killing effect of human effector cells and VCZ. At 0.01 and 0.05 microg ml(-1) of VCZ, G-CSF or GM-CSF enhanced PMN killing to 92% and 93% or 87% and 94%, respectively. GM-CSF enhanced both mono and MDM with VCZ at 0.01 and 0.05 microg ml(-1) in killing Cn to 62% and 86%, and 61% and 84%, respectively. These results suggest that VCZ would have good efficacy in the treatment of Cn infection in humans. Furthermore, VCZ would have enhanced efficacy in clinical settings where either G-CSF or GM-CSF was being used.

Antifungal Agents↗
PubMed1999

Comparison of interferon-gamma, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor for priming leukocyte-mediated hyphal damage of opportunistic fungal pathogens.

Proinflammatory cytokines have been proposed as adjunctive therapeutic agents to enhance the host immune response during infections caused by opportunistic fungi. The study compared the differential in vitro priming effects of interferon-gamma (IFN-gamma), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) on hyphal damage of opportunistic fungi mediated by isolated neutrophils (polymorphonuclear leukocytes, PMNL) and buffy coat cells (polymorphonuclear leukocytes/peripheral blood mononuclear cells, PMNL/PBMC) from healthy donors. IFN-gamma (1000 U/mL) effectively primed both PMNL and PMNL/PBMC for enhanced hyphal damage of Aspergillus fumigatus, Fusarium solani, and Candida albicans. G-CSF (100 ng/mL) increased hyphal damage mediated by both PMNL and PMNL/PBMC against F. solani, and GM-CSF (100 ng/mL) augmented the antifungal activity of PMNL/PBMC against hyphal forms of both F. solani and C. albicans. IFN-gamma may be superior to G-CSF or GM-CSF for enhancing the microbicidal activity of PMNL and PMNL/PBMC against opportunistic fungi.

Fungi↗
PubMed1998

Dexamethasone enhances macrophage colony stimulating factor- and granulocyte macrophage colony stimulating factor-stimulated proliferation of bone marrow-derived macrophages.

Glucocorticoids are effective repressors of the immune system. We have examined the effect of glucocorticoids on the proliferation of murine macrophages. Dexamethasone by itself did not affect proliferation of differentiated or undifferentiated bone marrow-derived macrophages (BMM) and elicited peritoneal macrophages. However, dexamethasone enhanced the proliferation induced by macrophage colony stimulating factor (M-CSF) of these cells. The effect of dexamethasone was not restricted to M-CSF-dependent proliferation. Similarly, dexamethasone enhanced granulocyte macrophage colony stimulating factor (GM-CSF)-dependent proliferation of BMM. In agreement, macrophages transfected with the glucocorticoid receptor showed an enhancement of M-CSF-dependent proliferation. The enhancement of proliferation by dexamethasone or the glucocorticoid receptor was abolished by RU 486, an antagonist of the glucocorticoid receptor. Moreover, the addition of antibodies against M-CSF inhibits the effect of dexamethasone, suggesting that dexamethasone increases the autocrine production of M-CSF. This only occurs when M-CSF or GM-CSF, which induce M-CSF, are present in the media. In tissues, dexamethasone may enhance macrophage proliferation and contribute to the resolution of the inflammatory states.

Animals↗
PubMed1992

Different accessory function for TH1 cells of bone marrow derived macrophages cultured in granulocyte macrophage colony stimulating factor or macrophage colony stimulating factor.

The ability of macrophages to stimulate immune responses is heterogeneous and may have influence on the type of the developing immune response. Therefore, in an attempt to define different functional states of mouse macrophages, we made use of the two macrophage growth factors: macrophage colony stimulating factor (M-CSF) and granulocyte macrophage colony stimulating factor (GM-CSF). Generation of macrophages from freshly isolated bone marrow cells in the presence of GM-CSF results in a population expressing profound antigen presenting function for mouse TH1 cells, resulting in strong lymphokine production and proliferation of the T cells. Furthermore, high amounts of a novel soluble cytokine active on mouse TH1 cells are generated during the interaction of TH1 cells with macrophages elicited with GM-CSF. In contrast, macrophages grown from bone marrow cells for at least 14 days in the presence of M-CSF express only minimal antigen-presenting function for TH1 cells. Treatment of such macrophages for 24 h with either IFN-gamma or GM-CSF allows the distinction between two further functional states. Those treated with IFN-gamma efficiently presented antigen towards TH1 cells. The T cells produced large amounts of lymphokines and proliferate well. However, synthesis of the novel soluble cytokine (active on TH1 cells) was not detectable. The generation of this mediator requires a short-term treatment with GM-CSF of macrophages developed in the presence of M-CSF prior to their interaction with TH1 cells.

Animals↗
PubMed1998

Comparison of neutrophil and monocyte function by microbicidal cell-kill assay in patients with cancer receiving granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or no cytokine after cytotoxic chemotherapy: a phase II trial.

Functional effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) were prospectively measured by harvesting blood samples from 51 oncology patients (21 who were receiving no cytokines, 14 receiving rhGM-CSF, and 16 who were receiving rhG-CSF) just before cytotoxic chemotherapy (baseline) immediately before the last cytokine dose (pre), 2 hours after the last cytokine dose (post), and 48 hours after the pre period (follow-up). Neutrophils and monocytes were separated and functional effects were measured by comparing cell-kill percentages, as determined by a microbial cell-kill assay against Staphylococcus aureus and Candida albicans. Optimal cell concentrations (2 x 10(6) monocytes/ml; 4 x 10(6) neutrophils/ml) and effector-to-cell ratios (1:50) were initially determined with blood samples harvested from 23 healthy volunteers. Results in oncology patients indicated that rhGM-CSF improved monocyte-killing activity against S. aureus at follow-up, compared with controls (p = 0.0094) and compared with monocytes from rhG-CSF-treated patients at the post period (p = 0.014). Cell-killing percentage of the rhGM-CSF-treated patients was also enhanced against C. albicans during the post period, compared with controls (p = 0.011) and rhG-CSF-treated patients (p = 0.067). Neutrophil activity was not altered by either cytokine. In conclusion, monocyte-induced microbial killing was enhanced in oncology patients receiving rhGM-CSF after cytotoxic chemotherapy, compared with patients receiving rhG-CSF or no cytokines. No differences in neutrophil activity were observed between patients receiving either cytokine.

Candida albicans↗
PubMed2000

Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome.

OBJECTIVE: To determine whether bronchoalveolar lavage fluid (BALF) from patients either at risk for the acute respiratory distress syndrome (ARDS) or with sustained ARDS modulates neutrophil apoptosis; to measure the BALF concentrations of the apoptosis inhibitors granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF) before and after the onset of ARDS; and to determine whether the BALF concentrations of G-CSF and/or GM-CSF are associated with clinical outcome. DESIGN: Prospective cohort study. SETTING: Tertiary university hospital. PATIENTS: Twenty patients at risk for ARDS and 45 patients with established ARDS. INTERVENTIONS: Patients at risk for ARDS underwent bronchoalveolar lavage within 24 hrs of being identified, then again 72 hrs later. Patients with ARDS underwent bronchoalveolar lavage within 24 hrs of meeting ARDS criteria, then again on days 3, 7, and 14 of the disease. MEASUREMENTS AND MAIN RESULTS: Normal peripheral blood neutrophil were incubated overnight in BALF from normal volunteers, from patients at risk for ARDS, or from patients with ARDS. neutrophil apoptosis was determined by flow cytometric analysis of annexin V binding. G-CSF and GM-CSF were measured in BALF by immunoassays. Compared with normal BALF, BALF from patients on days 1 and 3 of ARDS inhibited neutrophil apoptosis, but BALF from patients at later stages of ARDS, or from patients at risk for ARDS, did not. The BALF concentrations of both G-CSF and GM-CSF were elevated early in ARDS and decreased toward later stages. Patients who lived had significantly higher concentrations of GM-CSF in the BALF than those who died. CONCLUSIONS: We conclude that the antiapoptotic effect of ARDS BALF on normal neutrophil is highest during early ARDS, and decreases during late ARDS. G-CSF and GM-CSF are present in BALF from patients with ARDS, and their concentrations parallel the antiapoptotic effect of ARDS BALF. These data support the concept that the life-span of neutrophil in the air spaces is modulated during acute inflammation. GM-CSF in the air spaces is associated with improved survival in patients with ARDS.

Adolescent↗
PubMed2000

Plasma granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor levels in critical illness including sepsis and septic shock: relation to disease severity, multiple organ dysfunction, and mortality.

OBJECTIVE: To define the circulating levels of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during critical illness and to determine their relationship to the severity of illness as measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score, the development of multiple organ dysfunction, or mortality. DESIGN: Prospective cohort study. SETTING: University hospital intensive care unit. PATIENTS: A total of 82 critically ill adult patients in four clinically defined groups, namely septic shock (n = 29), sepsis without shock (n = 17), shock without sepsis (n = 22), and nonseptic, nonshock controls (n = 14). INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: During day 1 of septic shock, peak plasma levels of G-CSF, interleukin (IL)-6, and leukemia inhibitory factor (LIF), but not GM-CSF, were greater than in sepsis or shock alone (p < .001), and were correlated among themselves (rs = 0.44-0.77; p < .02) and with the APACHE II score (rs = 0.25-0.40; p = .03 to .18). G-CSF, IL-6, and UF, and sepsis, shock, septic shock, and APACHE II scores were strongly associated with organ dysfunction or 5-day mortality by univariate analysis. However, multiple logistic regression analysis showed that only septic shock remained significantly associated with organ dysfunction and only APACHE II scores and shock with 5-day mortality. Similarly, peak G-CSF, IL-6, and LIF were poorly predictive of 30-day mortality. CONCLUSIONS: Plasma levels of G-CSF, IL-6, and LIF are greatly elevated in critical illness, including septic shock, and are correlated with one another and with the severity of illness. However, they are not independently predictive of mortality, or the development of multiple organ dysfunction. GM-CSF was rarely elevated, suggesting different roles for G-CSF and GM-CSF in human septic shock.

APACHE↗
PubMed2002

Comparison of recombinant granulocyte colony-stimulating factor, recombinant human granulocyte-macrophage colony-stimulating factor and placebo for treatment of septic preterm infants.

BACKGROUND: To reduce morbidity and mortality adjuvant cytokine therapy was administered to septic neonates with variable results. The objective of this case series was to compare the effectiveness of recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) and recombinant granulocyte colony-stimulating factor (rG-CSF) with that of placebo in correcting neutropenia induced by sepsis. METHODS: Symptomatic, septic premature neonates with or without a positive blood culture were eligible. Twenty-eight patients were randomized: 10 received rG-CSF (5 microg/kg/dose i.v. twice a day); 10 received rhuGM-CSF (4 microg/kg/dose i.v. twice a day) and 8 received placebo for a maximum of 7 days, or until an absolute neutrophil count (ANC) of 10,000 cells/mm was reached. RESULTS: A significant increase in the ANC above the baseline was present on Day 2 in the rG-CSF group (P = 0.015) and on Day 5 in the rhuGM-CSF (P = 0.002) and placebo (P = 0.027) groups. The ANC of the rG-CSF group was significantly above that in the rhuGM-CSF and placebo groups on Day 7 (P = 0.03). Mortality and neonatal intensive care unit morbidity was not significantly different between the groups. CONCLUSION: The neutrophil count in the rG-CSF-treated group increased significantly faster than that in the placebo or rhuGM-CSF group.

Anti-Infective Agents↗
PubMed2002

Comparison between granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor in the mobilization of peripheral blood stem cells.

Peripheral blood stem cells (PBSC) have become the preferred source of stem cells for autologous transplantation because of the technical advantage and the shorter time to engraftment. Mobilization of CD34+ into the peripheral blood can be achieved by the administration of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or both, either alone or in combination with chemotherapy. G-CSF and GM-CSF differ somewhat in the number and composition of PBSCs and effector cells mobilized to the peripheral blood. The purpose of this review is to give a recent update on the type and immunologic properties of CD34+ cells and CD34+ cell subsets mobilized by G-CSF or GM-CSF with emphasis on (1) relative efficacy of CD34+ cell mobilization; (2) relative toxicities of G-CSF and GM-CSF as mobilizing agents; (3) mobilization of dendritic cells and their subsets; (4) delineation of the role of adhesion molecules, CXC receptor 4, and stromal cell-derived factor-1 signaling pathway in the release of CD34+ cell to the peripheral blood after treatment with G-CSF or GM-CSF.

Animals↗
PubMed2002

Activation of human gingival epithelial cells by cell-surface components of black-pigmented bacteria: augmentation of production of interleukin-8, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor and expression of intercellular adhesion molecule 1.

Black-pigmented anaerobic bacteria, such as Porphyromonas gingivalis and Prevotella intermedia, are amongst the predominant bacteria in periodontal pockets and have been implicated in periodontal diseases. To elucidate the roles of gingival keratinocytes, which are the first cells encountered by oral bacteria in periodontal diseases, human gingival keratinocytes in primary culture were stimulated with cell-surface components of P gingivalis and Pr. intermedia. A glycoprotein fraction from Pr. intermedia (PGP) clearly augmented the release of interleukin-8, granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor, as determined by enzyme-linked immunosorbent assay. This PGP also induced expression of intercellular adhesion molecule-1 (ICAM-1), as determined by flow cytometry. The augmentation of mRNA expression for these molecules was also confirmed by reverse transcription PCR. In contrast, lipopolysaccharide (LPS) from Pr. intermedia and Escherichia coli was completely inactive in these assays. LPS fraction and purified fimbriae from P gingivalis exhibited weak activities. Cytokine production and ICAM-1 expression by gingival keratinocytes might cause accumulation and activation of neutrophils in the epithelium and, therefore, may be involved in the initiation and development of inflammation in periodontal tissues.

Cells, Cultured↗
PubMed1993

Enhancement of cytosine arabinoside cytotoxicity by granulocyte/macrophage colony-stimulating factor and granulocyte colony-stimulating factor in a human myeloblastic leukemia cell line.

Enhancement of the cytotoxicity of cytosine arabinoside (ara-C) by granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), and the mechanisms involved, were studied in the AML-193 human leukemia cell line. AML-193 cells require GM-CSF and G-CSF(CSFs) for optimum growth, and 24 h deprivation of CSFs decreased DNA synthesis measured in terms of 3H-thymidine incorporation. The DNA synthesis gradually recovered upon addition of CSFs. To examine the sensitivity to ara-C under different growth conditions, two groups of cell suspensions, one pretreated with CSFs after 24 h deprivation (CSFs(+) cells), and the other held continuously under CSFs-free conditions (CSFs(-) cells), were exposed to 1.0 microgram/ml of ara-C for 16 h. In clonogenic assays, CSFs(+) cells showed higher sensitivity to ara-C than CSFs(-) cells. These cell groups showed no significant difference in ara-C triphosphate accumulation or retention, though the amount of ara-C incorporated into the acid-insoluble fraction was two times greater in CSFs(+) cells than CSFs(-) cells, and that difference became even clearer in the retention pools. These data suggest that the enhancement of cytotoxicity by CSFs was due to the promotion of ara-C incorporation into DNA as a result of an increase of the cell fraction in the S phase.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Cyclooxygenase-2 inhibitor NS-398 suppresses cell growth and constitutive production of granulocyte-colony stimulating factor and granulocyte macrophage-colony stimulating factor in lung cancer cells.

We previously established two lung cancer cell lines, OKa-C-1 and MI-4, which constitutively produce abundant granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage-colony stimulating factor (GM-CSF). Inflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta stimulated the expression of G-CSF, GM-CSF, and cyclooxygenase (COX)-2 in the two cell lines. It is known that increased COX-2 activity promotes tumor growth and induces G-CSF and GM-CSF expression in non-malignant cells, and that selective COX-2 inhibitors inhibit the growth of some types of malignant cells. Therefore, we hypothesized that inhibition of COX-2 activity might suppress constitutive production of G-CSF or GM-CSF in addition to reducing the growth of malignant cells. We confirmed that the selective COX-2 inhibitor, NS-398 suppressed the constitutive production of G-CSF and GM-CSF, and the cell growth in both OKa-C-1 and MI-4 cell lines. Prostaglandin E2 (PGE2) reversed the inhibitions of G-CSF and GM-CSF expression, as well as cell growth, by NS-398. This result confirms that the effects of NS-398 are based on the inhibition of COX activity. Some studies have indicated that nuclear factor kappa B (NF-kappaB) or MAPK (mitogen-activated protein kinase) activation is related to upregulation of G-CSF, GM-CSF or COX-2 expression in some types of cells. Therefore, we examined if the actions of NS-398 might be mediated by the MAP kinase pathway or NF-kappaB activity in OKa-C-1 and MI-4 cells. We found that NS-398 inhibits G-CSF and GM-CSF production and cell growth through an extracellular signal-regulated kinase kinase (MEK) signaling pathway in these cell lines. The prognosis of non-small cell lung cancer showing G-CSF gene expression is significantly worse. G-CSF overproduction by tumor cells is observed at an advanced clinical stage. Our findings imply that a COX-2 inhibitor might improve the prognosis of patients with lung cancer through the reduction of G-CSF or GM-CSF.

Cell Division↗
PubMed1991

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in serum during induction treatment of acute leukaemia.

Granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are increasingly used to stimulate granulopoiesis in neutropenic patients but in most cases without any knowledge of the endogenous CSF-levels. With the purpose to define serum levels of GM-CSF and G-CSF during induction chemotherapy and haematological reconstitution in patients with acute leukaemia we have used enzyme-linked immunosorbent assay (ELISA) techniques to measure these growth factors in 18 patients with acute myeloid leukaemia (AML) and eight patients with acute lymphoblastic or undifferentiated leukaemia (ALL/AUL). G-CSF above 0.05 ng/ml was detected in 54% of the analysed AML samples, median 0.29 (range 0.05-2.80) ng/ml; and in 40% of analysed ALL/AUL samples, median 0.09 (range 0.05-3.00) ng/ml. In patients with AML there was a clear correlation between an elevated serum concentration of G-CSF and documented infections. On the other hand, 15/18 of the patients with acute myeloid leukaemia and 8/8 patients with ALL/AUL had non-detectable levels of GM-CSF (less than 0.10 ng/ml). Two patients had measurable levels of GM-CSF in all samples, median 0.71 (range 0.26-1.18) ng/ml and in these patients the levels successively decreased during and after chemotherapy and did not increase in response to infections. In normals detectable levels of GM-CSF were found in 2/35 individuals and G-CSF in 0/10 individuals.

Acute Disease↗